title: RAGE signaling contributes to neuroinflammation in infantile neuronal ceroid lipofuscinosis.
abstract: Palmitoyl-protein thioesterase-1 (PPT1) deficiency causes infantile neuronal ceroid lipofuscinosis (INCL), a devastating childhood neurodegenerative storage disorder. We previously reported that neuronal apoptosis in INCL is mediated by endoplasmic reticulum-stress. ER-stress disrupts Ca(2+)-homeostasis and stimulates the expression of Ca(2+)-binding proteins. We report here that in the PPT1-deficient human and mouse brain the levels of S100B, a Ca(2+)-binding protein, and its receptor, RAGE (receptor for advanced glycation end-products) are elevated. We further demonstrate that activation of RAGE signaling in astroglial cells mediates pro-inflammatory cytokine production, which is inhibited by SiRNA-mediated suppression of RAGE expression. We propose that RAGE signaling contributes to neuroinflammation in INCL.
authors.affiliation: Section on Developmental Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1830, United States.
authors.forename: Arjun
authors.initials: A
authors.lastname: Saha
authors.forename: Sung-Jo
authors.initials: SJ
authors.lastname: Kim
authors.forename: Zhongjian
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Lee
authors.forename: Chinmoy
authors.initials: C
authors.lastname: Sarkar
authors.forename: Pei-Chih
authors.initials: PC
authors.lastname: Tsai
authors.forename: Anil B
authors.initials: AB
authors.lastname: Mukherjee
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D004660:Encephalitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D015398:Signal Transduction; D013869:Thiolester Hydrolases / Q000235:genetics; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D009414:Nerve Growth Factors; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; C579159:S100b protein, mouse; D019061:src-Family Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase